Cardiovascular disease (CVD) is the leading cause of death worldwide, and results in a high societal and economic burden. While improvements in interventional surgical approaches continue to better patient prognosis, preventative treatments for CVD are underdeveloped and represent an unmet need. As a preventative, exercise has been reported to effectively reduce cardiovascular morbidity and mortality. Therefore, understanding the mechanisms of exercise at the genetic level in the heart is crucial to developing therapies that mimic exercise benefits. Furthermore, targeting these therapies to specific cell types is desirable to prevent off-target effects. To this end, this proposal focuses on a molecule (Sprr2b) that is absent from all cell types in exercise-induced physiologic hypertrophy, and present only in cardiac fibroblasts (CF) in pathologic hypertrophy leading to heart failure (a purely maladaptive gene). Exciting preliminary data reveals the following about Sprr2b in CF: 1) it is inversely regulated in physiologic and pathologic hypertrophy, 2) in the heart it is exclusively expressed in CF, 3) its expression is synergistically induced by TGF?1 and ROS, and 4) it drives cell cycle progression, survival signaling, and proliferation of CF. This final finding is of particular interest, as CF proliferation underlies fibrotic remodeling during heart failure, and to date the only known function of Sprr2b is in the formation of the cornified envelope (CEnv), a specialized barrier function and death pathway. I have also shown for the first time that Sprr2b interacts with USP7, which stabilizes USP7-MDM2 interaction and subsequent MDM2-dependent degradation of p53, leading to the observed changes in cell cycle. This interaction was dependent on phosphorylation at Y67, and the Y67F loss-of-function mutant normalized CF proliferation. The major hypothesis to be tested in this proposal is that through novel protein-protein interactions in CF during pathologic hypertrophy, Sprr2b induces proliferation, survival, and activation of CF, leading to fibrotic remodeling during heart failure.